Killer Cell Lectin-like Receptor G1 Inhibits NK Cell Function through Activation of Adenosine 5'-Monophosphate-Activated Protein Kinase.
Killer Cell Lectin-like Receptor G1 Inhibits NK Cell Function through Activation of Adenosine 5'-Monophosphate-Activated Protein Kinase.
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DOI：
10.4049/jimmunol.1600590
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发表时间：
2016-10-01
期刊：
影响因子：
--
通讯作者：
Akbar AN
中科院分区：
文献类型：
--
作者：
Müller-Durovic B;Lanna A;Covre LP;Mills RS;Henson SM;Akbar AN
NK细胞是抵御感染和转化细胞的第一道防线。缺陷NK细胞活性已被证明增加对病毒感染的易感性和降低肿瘤免疫监视。随着年龄的增长，传染性疾病和恶性肿瘤的发病率急剧上升，这表明NK细胞功能受损可能导致这些个体的疾病。我们发现，在70岁以上的个体中，高表达抑制性杀伤细胞凝集素样受体G1 （KLRG1）的NK细胞频率增加。KLRG1在衰老中的作用尚不清楚，KLRG1诱导的NK细胞功能抑制的机制尚不完全清楚。在这里，我们报道了高KLRG1表达的NK细胞自发激活代谢传感器amp活化蛋白激酶（AMPK）， AMPK的激活负性调节NK细胞功能。在这些细胞中，先前存在的AMPK活性通过连接KLRG1进一步放大，从而导致受体内化并允许与AMPK相互作用。我们发现KLRG1激活AMPK是通过阻止其被蛋白磷酸酶PP2C抑制去磷酸化，而不是诱导重新激活激酶。最后，抑制KLRG1或AMPK均可阻止KLRG1诱导的AMPK活化和NK细胞毒性、细胞因子分泌、增殖和端粒酶表达的降低。这种新的信号通路将代谢感知、效应功能和细胞分化与抑制受体信号联系起来，可能被利用来增强衰老过程中的NK细胞活性。
NK cells are the first line of defense against infected and transformed cells. Defective NK cell activity has been shown to increase susceptibility for viral infections and reduce tumor immune-surveillance. With age, the incidence of both infectious diseases and malignancy rises dramatically suggesting that impaired NK cell function might contribute to disease in these individuals. We found an increased frequency of NK cells with high expression of the inhibitory Killer Cell Lectin-like Receptor G1 (KLRG1) in individuals >70 years. The role of KLRG1 in ageing is not known and the mechanism of KLRG1-induced inhibition of NK cell function is not fully understood. Here we report that NK cells with high KLRG1 expression spontaneously activate the metabolic sensor AMP-activated protein kinase (AMPK) and that activation of AMPK negatively regulates NK cell function. Pre-existing AMPK activity is further amplified by ligation of KLRG1 in these cells, which leads to internalization of the receptor and allows interaction with AMPK. We show that KLRG1 activates AMPK by preventing its inhibitory de-phosphorylation by protein phosphatase PP2C rather than inducing de novo kinase activation. Finally, inhibition of either KLRG1 or AMPK prevented KLRG1-induced activation of AMPK and reduction in NK cell cytotoxicity, cytokine secretion, proliferation and telomerase expression. This novel signaling pathway links metabolic sensing, effector function and cell differentiation with inhibitory receptor signaling that may be exploited to enhance NK cell activity during ageing.
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影响因子：
3.9
作者：
Borrego, F;Alonso, MC;Solana, R
通讯作者：
Solana, R
影响因子：
7.8
作者：
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20.3
作者：
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Akbar, Arne N.
DOI：
10.1111/j.1532-5415.1996.tb01862.x
发表时间：
1996-08-01
影响因子：
6.3
作者：
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通讯作者：
Monroe, PW
影响因子：
30.5
作者：
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通讯作者：
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